1. Field of the Invention
The invention relates to the fields of dermatology, cell biology and cancer. More specifically, the invention relates to the fields of drug discovery, particularly the biology of skin pigmentation, and cancer.
2. Summary of the Related Art
Melanocytes are pigment-producing cells that are principle targets for the treatment of hypo-pigmentation, hyper-pigmentation, and melanoma. The pink-eyed dilution protein (P), which is produced in melanocytes, is necessary for the production of both cutaneous and ocular eumelanin, but the precise function for the P protein is not known. Mutations in the pink-eyed dilution gene result in the most common form of albinism worldwide (The Metabolic and Molecular Basis of Inherited Disease. Scriver et al., eds, McGraw-Hill Professional Publishing, New York, 8th Ed. (2000); pp. 4353-4392; ISBN: 0079130356). Affected individuals have hypopigmented skin, hair and eyes (Manga et al., J. Dermatol. 26:738-747 (1999)), and are thus at increased risk of developing UV-induced carcinomas (Kromberg et al., Clin. Genet. 36:43-52 (1989)).
Several authors have suggested that P protein functions as a tyrosine transporter by pumping tyrosine into the melanosome, where it is converted into melanin by tyrosinase activity (see, e.g., Rinchik et al., Nature 361:72-76 (1993)). Contradicting this suggestion, it has been found that tyrosine uptake by melanosomes is virtually the same in P-null and wild-type melanocytes (Gahl et al., Pigment. Cell. Res. 8:229-233 (1995)).
This observation has led other authors to hypothesize that P protein is necessary for the transport of some other small molecule, which is necessary for melanogenesis, into melanosomes (Nordlund et al., eds, The Pigmentary System: Physiology and Pathophysiology, Oxford University, New York (1998) pp. 217-229) or in controlling the trafficking of melanosomal proteins (Manga et al., Pigment Cell Res. 14:362-367 (2001)).
Interestingly, a number of melanoma cell lines fail to express the pink-eyed dilution protein (P)(Id.). Human melanoma is the result of the malignant transformation of melanocytes. The incidence rates for this form of neoplasia have been reported to be increasing by a factor of about 15 over the last 60 years (Gilchrest et al., New England J. Med. 340:1341-1348 (1999).
Advanced malignant melanomas have a poor prognosis, particularly since they show increased resistance to many of the currently available chemotherapeutic agents. The mechanisms used by melanomas to escape induction of programmed cell death, or apoptosis, appear to vary. These mechanisms include transport of chemotherapeutic drugs to remove them from their target sites, changes in enzyme activation that affect cellular detoxification, and modulation of the apoptosis pathway itself (Helmbach et al., Int. J. Cancer 93:617-622 (2001)).
A variety of treatments for melanoma have been proposed, but the disease is still very difficult to treat in advanced stages. For example, U.S. Pat. No. 5,066,489 describes a combination therapy for the treatment of melanoma; U.S. Pat. No. 5,731,325 describes the treatment of melanomas with thalidomide alone or in combination with other anti-melanoma agents, and U.S. Pat. No. 6,291,196 discloses melanoma and prostate cancer specific antibodies for immunodetection and immunotherapy of these diseases.
Thus, there continues to be a need for improved methods for the treatment of cancer, particularly melanoma.
Many individuals desire to increase or decrease the level of body pigmentation in whole or part. Moreover, medical conditions based on hyper- or hypo-pigmentation also require treatments that are effective at increasing or decreasing the amount of pigment in the skin. A number of compositions are known to lighten skin. For example, hydroquinone is a well-known active substance used for skin de-pigmentation (e.g., see U.S. Pat. No. 6,139,854). Lactoferrin hydrolyzates have been used as a tyrosinase inhibitory agent (e.g., U.S. Pat. Nos. 5,214,028 and 5,389,611), and certain resorcinol derivatives have been used as skin lightening agents (U.S. Pat. No. 6,132,740).
The P protein is one possible target for the treatment of hypo- and hyper-pigmentation. For example, PCT patent publication WO 01/01131 A1 describes methods for the identification of agonists and antagonists of P protein function. These methods are not based on cell viability or cell glutathione content, but rather are based on identifying compounds that affect tyrosinase activity in a P protein dependent fashion or measuring the production of melanin.
There remains a need in the art for more effective and efficient methods of inhibiting melanin production. The need for new and improved methods for lightening skin is evident in view of the cosmetic industry's estimate that the market for skin lighteners worldwide exceeds well over one billion dollars a year. In addition, there is also a need for agents that increase pigmentation for the purpose of providing “safe tanning” or for the treatment of hypopigmentation or the treatment of various forms of albinism. Thus, there is a continuing need for the development of improved agents that limit or inhibit pigmentation in the skin.